Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders.

Neurological and psychiatric disorders, including substance use disorders, share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral/quantitative brain-related traits (n = 12,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e., medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.

Structure effects of Pt15 clusters for the oxygen reduction reaction: first-principles calculations.

In the present work, the lowest energy structures and electronic properties of Pt15 clusters are investigated using molecular dynamics simulations. The results showed that the most stable configuration is a capped pyramidal structure, which is 0.8 kal mol-1 lower in energy than a layered structure previously reported [V. Kumar and Y. Kawazoe, Evolution of Atomic and Electronic Structure of Pt Clusters: Planar, Layered, Pyramidal, Cage, Cubic, and Octahedral Growth, Phys. Rev. B: Condens. Matter Mater. Phys., 2008, 77, 205418.]. The result is further confirmed by using both the PW91/cc-pVDZ-PP and PBE/PW approaches including the other representative isomers for Pt15. Due to the interesting structure arrangements found, we have investigated the catalytic activities for the oxygen reduction reaction. We found that the most stable Pt15 clusters are plausible catalyts for the ORR according to their interaction with oxygen species, which is consistent with experiments of Pt clusters with atomicity below 20. The results of the structure, electronic, adsorption and vibrational properties of the clusters are provided.

Correction: Structure effects of Pt15 clusters for the oxygen reduction reaction: first-principles calculations.

Correction for 'Structure effects of Pt15 clusters for the oxygen reduction reaction: first-principles calculations' by Peter L. Rodríguez-Kessler et al., Phys. Chem. Chem. Phys., 2023, https://doi.org/10.1039/d2cp05188e.

Structural and electronic properties for Be-doped Ptn (n = 1-12) clusters obtained by DFT calculations.

In this work, we have performed a computational study on the structure and electronic properties for Be-doped Ptn (n = 1-12) clusters in the framework of density functional theory (DFT). The most stable structures of the clusters are obtained by a structure search procedure based in simulated annealing. The results show that the PtnBe clusters adopt compact structure motifs with Be situated at the edge sites while only in Pt11Be the Be atom occupies the center site. The energetic parameters showed that Pt5Be, Pt7Be and Pt10Be are the most stable ones. The PtnBe clusters with (n = 5-7) have similar vertical ionization potential (vIP) and vertical electron affinity (vEA) parameters compared to the unary Pt clusters, while Pt9Be and Pt11Be have the higher vEA values. In particular, the d-band center is slightly higher for the doped clusters, suggesting an enhanced reactivity. The σ-holes are found more remarkable for the doped clusters, which are situated in the Be dopant and low coordinated Pt sites. The data on the infrared spectra of the clusters is also provided and showed a significant blue shift due to the vibrational modes of the Be atom. These results are useful for understanding the fundamental properties of Be-doped Ptn clusters in the subnanometer region.

[Translational genetics; expectations for eating disorders and other psychiatric disorders]. / Translationele genetica: verwachtingen voor eetstoornissen en andere psychiatrische stoornissen.

BACKGROUND: Translational (genetic) research focuses on the translation of preclinical research into practice. While many genetic studies have been conducted in recent years, the results do not simply translate to the clinic.
AIM: To visualize the steps through which translational genetic research contributes to the unraveling of the biological backgrounds of psychiatric disorders, in particular of eating disorders.
METHOD: Literature review.
RESULTS: Genetic studies have unraveled a mechanism underlying the hunger and satiety system. There is hope that genome-wide studies of eating disorders will lead to identification of neural circuits in which associated genes cluster. New techniques, such as opto- and chemogenetics, provide the opportunity to define the precise role of these circuits in eating disorders.
CONCLUSION: New techniques in molecular neuroscience allow the unravelling of the complexity of how the brain works and some of those techniques (such as chemogenetics) are being further developed for application in humans. However, it will be years before we can definitively translate this into the treatment of psychiatric disorders.
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Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.

Systematic cluster growth: a structure search method for transition metal clusters.

The systematic cluster growth (SCG) method is a biased structure search strategy based on a seeding process for investigating the structural evolution and growth pattern of transition metal clusters. In SCG, a set of initial structures with size n are constructed based on the equilibrium structures of the preceding n- 1 cluster isomers by adding a single atom at all inequivalent binding sites. This strategy requires a relatively low number of evaluations for global minima localization on the potential energy surface, allowing its application in first-principles calculations. The performance of SCG is tested by using the Lennard Jones (LJ) potential energy surface. The 93.7% of the best-known solutions for Lennard Jones clusters were found for n≤ 80 by using a relatively low number of local optimizations. Most importantly, by using SCG combined with DFT calculations (SCG-DFT), we revisit and provide the ground state structures and growth pattern for transition metal clusters TMn (where TM = Ti, Ni, Cu, Ag, Pt; and n = 6-14). The application of the code for doped clusters is also discussed. A detailed description of the present method for generating the structures of the clusters is provided.

On the structure and reactivity of PtnCun (n = 1-7) alloy clusters.

The structure, electronic and reactivity properties of PtnCun (n = 1-7) clusters are investigated in the framework of density functional theory (DFT). The most stable forms of the clusters are obtained by a structure search procedure based in simulated annealing. The results show that the PtnCun cluster alloys adopt layered structure motifs with segregation of the Cu and Pt species. The total magnetic moments of the clusters adopt the low spin configuration. The bimetallic cluster reactivity is investigated by using the ionization potential, electron affinity, and the d-band center, respectively. The results show that the PtnCun clusters with (n = 5-7) have similar vIP and vEA parameters compared to the unary Pt clusters, but the d-band center is slightly higher suggesting an enhanced reactivity for the bimetallic clusters. On the other hand, the molecular electrostatic potential shows that the Cu species increase the available active sites on the cluster surface. The data on the infrared spectra of the clusters is also provided. These results are useful to understand the fundamental properties of Pt-M bimetallic alloys in the subnanometer region.

Reply to 'Comment on "Structural characterization, reactivity, and vibrational properties of silver clusters: A new global minimum for Ag16"' by P. V. Nhat, N. T. Si, L. V. Duong and M. T. Nguyen, Phys. Chem. Chem. Phys., 2021, 23, DOI: D1CP00646K.

Recently, P. V. Nhat et al., have discussed and commented on our article (DOI: 10.1039/D0CP04018E) for the case of the most stable structure of Ag15. They have found a new most stable structure (labeled as 15-1) in comparison to the putative global minimum reported by us, which is a four layered 1-4-6-4 stacking structure with a C2v point group (15-2). In this reply, we have performed a larger structure search which allowed us to confirm the results of Nhat et al. The results show the existence of multiple isoenergetic isomers with similar structure motifs for the Ag15 system, increasing the problem complexity to locate the global minimum. The results in regard to the structure and electronic properties of the new lowest energy structure are discussed.

Structural characterization, reactivity, and vibrational properties of silver clusters: a new global minimum for Ag16.

In the present work, the lowest energy structures and electronic properties of Agn clusters up to n = 16 are investigated using a successive growth algorithm coupled with density functional theory calculations (DFT). In the literature, a number of putative global minimum structures for silver clusters have been reported by using different approaches, but a comparative study for n = 15-16 has not been undertaken so far. Here, we perform a comparative study using the PW91/cc-pVDZ-PP level to more precisely determine the optimal configuration. For Ag15, the most stable configuration is a four layered 1-4-6-4 stacking structure with C2v symmetry. For Ag16 a new most stable form is found with a 1-4-2-5-1-3 stacking structure in the singlet state, slightly more stable than the putative global minimum reported. By means of the electrostatic potential, the new putative global minimum has been found to be more reactive, and the active sites of the clusters were identified and confirmed with the interaction energy. The electronic and vibrational properties are found to be in good agreement with the available experimental data. Theoretical data on the infrared spectra of the clusters is also provided.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

The association of emotion-driven impulsiveness, cognitive inflexibility and decision-making with weight status in European adolescents.

OBJECTIVE: To explore the association between emotion-driven impulsiveness, cognitive inflexibility, decision-making and weight status as reflected in body mass index (BMI) z-score (zBMI) in European adolescents. METHODS: In total, 3354 adolescents aged between 12 and 18 years from the I.Family cohort completed the questionnaire-based negative urgency subscale from the UPPS-P Impulsive Behavior Scale to measure emotion-driven impulsiveness in 2013/2014. Furthermore, 1584 adolescents completed the computer-based Bergs Card Sorting Test to measure cognitive inflexibility, and 1780 adolescents completed the Hungry Donkey Test to assess decision-making ability. Anthropometric variables were measured objectively; confounding variables (age, sex, socioeconomic status and country) were assessed using a questionnaire. Mixed-effect regression analyses were conducted for each outcome of the test or questionnaire as a predictor with standardised BMI (zBMI) as the dependent variable in order to investigate association between markers of cognitive functioning and zBMI. RESULTS: After controlling for confounders, results showed that emotion-driven impulsiveness (ß=0.18, 95% confidence interval (CI): 0.13 to 0.24, P<0.001) and cognitive inflexibility (ß=0.01, 95% CI: 0.002 to 0.02, P=0.016) were positively associated with zBMI. However, decision-making ability was not significantly related to zBMI (ß=0.001, 95% CI: -0.001 to 0.003, P=0.47). CONCLUSIONS: More emotion-driven impulsiveness and reduced cognitive flexibility were associated with a higher zBMI in adolescents across Europe. These results may indicate that being impulsive in negative situations and having difficulties changing mental sets increase the susceptibility for unhealthy weight development. Reducing impulsivity and training cognitive flexibility seem promising targets for the prevention and intervention programmes of obesity.

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Does activation of midbrain dopamine neurons promote or reduce feeding?

BACKGROUND: Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake. METHODS: Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats. RESULTS: Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour. CONCLUSIONS: Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviour.

Role of leptin in energy expenditure: the hypothalamic perspective.

The adipocyte-derived hormone leptin is a peripheral signal that informs the brain about the metabolic status of an organism. Although traditionally viewed as an appetite-suppressing hormone, studies in the past decade have highlighted the role of leptin in energy expenditure. Leptin has been shown to increase energy expenditure in particular through its effects on the cardiovascular system and brown adipose tissue (BAT) thermogenesis via the hypothalamus. The current review summarizes the role of leptin signaling in various hypothalamic nuclei and its effects on the sympathetic nervous system to influence blood pressure, heart rate, and BAT thermogenesis. Specifically, the role of leptin signaling on three different hypothalamic nuclei, the dorsomedial hypothalamus, the ventromedial hypothalamus, and the arcuate nucleus, is reviewed. It is known that all of these brain regions influence the sympathetic nervous system activity and thereby regulate BAT thermogenesis and the cardiovascular system. Thus the current work focuses on how leptin signaling in specific neuronal populations within these hypothalamic nuclei influences certain aspects of energy expenditure.

Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin.

BACKGROUND/OBJECTIVES: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. SUBJECTS/METHODS: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. RESULTS: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). CONCLUSIONS: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling.

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

shRNA-induced saturation of the microRNA pathway in the rat brain.

RNA interference (RNAi) is a powerful strategy for unraveling gene function and for drug target validation, but exogenous expression of short hairpin RNAs (shRNAs) has been associated with severe side effects. These may be caused by saturation of the microRNA pathway. This study shows degenerative changes in cell morphology and intrusion of blood vessels after transduction of the ventromedial hypothalamus (VMH) of rats with a shRNA expressing adeno-associated viral (AAV) vector. To investigate whether saturation of the microRNA pathway has a role in the observed side effects, expression of neuronal microRNA miR-124 was used as a marker. Neurons transduced with the AAV vector carrying the shRNA displayed a decrease in miR-124 expression. The decreased expression was unrelated to shRNA sequence or target and observed as early as 1 week after injection. In conclusion, this study shows that the tissue response after AAV-directed expression of a shRNA to the VMH is likely to be caused by shRNA-induced saturation of the microRNA pathway. We recommend controlling for miR-124 expression when using RNAi as a tool for studying (loss of) gene function in the brain as phenotypic effects caused by saturation of the RNAi pathway might mask true effects of specific downregulation of the shRNA target.